Tyrosine Nitration of Prostacyclin Synthase

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DESCRIPTION (Applicant?s abstract):Proinflammation is an important process in the development of atherosclerotic lesions and other pathophysiological conditions. In atherosclerotic lesions, peroxynitrite, which is formed by the reaction of nitric oxide and superoxide, nitrates proteins on tyrosine residues. This project has two aims that will test the hypothesis that peroxynitrite activates a proinflammatory state in endothelium by nitrating and inactivating prostacyclin synthase. This key enzyme in endothelium is unusually susceptible to peroxynitrite nitration at tyrosine 430 near its active site. Specific aim 1 is to use the powerful methodology of phage display of single chain antibodies to develop new antibodies that recognize the small nitrotyrosine epitope, as well as nitrated tyrosine 430 in prostacyclin synthase. Specific aim 2 is to assess whether shear stress also nitrates and inactivates prostacyclin synthase, resulting in the increase of proinflammatory prostacyclin precursor, PGH2. .